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0028

Chromium(III), insoluble salts;
CASRN 16065-83-1 (09/03/1998)

Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data, as outlined in the IRIS assessment development process. Sections I (Health Hazard Assessments for Noncarcinogenic Effects) and II (Carcinogenicity Assessment for Lifetime Exposure) present the conclusions that were reached during the assessment development process. Supporting information and explanations of the methods used to derive the values given in IRIS are provided in the guidance documents located on the IRIS website.

STATUS OF DATA FOR Chromium(III), insoluble salts

File First On-Line 01/31/1987

Category (section)

Status

Last Revised

Oral RfD Assessment (I.A.)

on-line

09/03/1998

Inhalation RfC Assessment (I.B.)

on-line

09/03/1998

Carcinogenicity Assessment (II.)

on-line

09/03/1998

_I.
Chronic Health Hazard Assessments for Noncarcinogenic Effects

_I.A.
Reference Dose for Chronic Oral Exposure (RfD)

The oral Reference Dose (RfD) is based on the assumption that thresholds
exist for certain toxic effects such as cellular necrosis. It is expressed
in units of mg/kg-day. In general, the RfD is an estimate (with uncertainty
spanning perhaps an order of magnitude) of a daily exposure to the human
population (including sensitive subgroups) that is likely to be without
an appreciable risk of deleterious effects during a lifetime. Please refer
to the Background Document for an elaboration of these concepts. RfDs
can also be derived for the noncarcinogenic health effects of substances
that are also carcinogens. Therefore, it is essential to refer to other
sources of information concerning the carcinogenicity of this substance.
If the U.S. EPA has evaluated this substance for potential human carcinogenicity,
a summary of that evaluation will be contained in Section II of this file.

Groups of 60 male and female rats were fed chromic oxide (Cr2O3) baked in bread at
dietary levels of 0, 1%, 2%, or 5%, 5 days/week for 600 feedings (840 total days). The primary
purpose of this study was to assess the carcinogenic potential of Cr2O3. Body weight and food
consumption were monitored. The average total amounts of ingested Cr2O3 were given as 360,
720, and 1,800 g/kg bw for the 1%, 2%, and 5% treatment groups, respectively. The animals
were maintained on control diets following termination of exposure until they became moribund
or died. All major organs were examined histologically. Other toxicologic parameters were not
mentioned explicitly, but may have included some or all of those deSRCibed for the accompanying
subchronic study (see below). No effects due to Cr2O3 treatment were observed at any dose
level.

Ivankovic and Preussmann (1975) also treated rats (both sexes, 12-19 rats/group) at
dietary levels of 0, 2%, or 5% Cr2O3 in bread, 5 days/week for 90 days. Food consumption and
body weight were monitored. Toxicologic parameters included serum protein, bilirubin,
hematology, urinalysis, organ weights, and histopathology. The only effects observed were
reductions (12%-37%) in the absolute weights of the livers and spleens of animals in the
high-dose group. Organ weights relative to body weight were not reported. The high dose is
equivalent to 1,400 mg/kg-day (dose converted using reported data).

Other subchronic oral studies show no indication of adverse effects attributable to
trivalent chromium compounds, but dose levels were considerably lower.

__I.A.3.
Uncertainty and Modifying Factors (Oral RfD)

UF = 100.

The factor of 100 represents two 10-fold decreases in mg/kg bw-day dose that account for
both the expected interhuman and interspecies variability to the toxicity of the chemical in lieu of
specific data.

MF = 10.

An additional 10-fold modifying factor is applied to reflect database deficiencies
including the lack of a study in a nonrodent mammal, lack of unequivocal data evaluating
reproductive impacts, and the concern regarding potential reproductive effects raised by the study
of Elbetieha and Al-Hamood (1997). The value of the modifying factor has not been changed
from the previous IRIS entry. The study of Elbetieha and Al-Hamood (1997) provides strong
support for the use of a 10-fold modifying factor to reflect uncertainty regarding potential
reproductive effects of Cr(III). The following additional uncertainties relate to the NOAEL
derived from the Ivankovic and Preussman (1975) study: 1) the effects observed in the 90-day
study were not explicitly addressed in the 2-year study; 2) the effect of the vehicle (baked bread)
on absorption of chromium is uncertain, and the relevance of this dosing regimen to exposures in
the environment is unclear; 3) animals were allowed to die naturally after feeding stopped (2
years) and only then was histology performed. Application of the 100-fold uncertainty factor
and 10-fold modifying factor to the adjusted NOAEL of 1,468 mg/kg-day gives the reference
dose of 1.5 mg/kg-day.

__I.A.4.
Additional Studies/Comments (Oral RfD)

Trivalent chromium is an essential element that potentiates insulin
action in peripheral tissue and is essential for lipid, protein, and fat
metabolism in animals and human beings. Chromium deficiency causes changes
in the metabolism of glucose and lipids and may be associated with maturity-onset
diabetes, cardiovascular diseases, and nervous system disorders (Anderson,
1993, 1995). The National Research Council has identified an estimated
safe and adequate daily dietary intake (ESADDI) for chromium of 50-200
µg/d (NRC, 1989), corresponding to 0.71-2.9 µg/kg/d for a 70 kg adult.
FDA has selected a Reference Daily Intake for chromium of 120 µg/d (DHHS,
1995).

Very limited data suggest that Cr(III) may have respiratory effects on
humans (see Section I.B). No data on chronic or subchronic effects of
inhaled Cr(III) in animals can be found. Adequate developmental toxicity
data do not exist, and there are inadequate data on reproductive effects.

Elbetieha and Al-Hamood (1997) reported impacts on fertility following
high doses (2,000-5,000 ppm in the drinking water) of chromium chloride
in mice; however, many of the observed effects did not occur in a clear
dose-dependent fashion. The authors did not indicate the amount of water
ingested by the animals, and only stated that water ingestion was reduced
in the treatment groups relative to the controls. Zahid et al. (1990)
fed mice trivalent chromium at concentrations of 100, 200, and 400 ppm
for 35 days in food and reported ambiguous levels of degeneration in the
outermost cellular layers of the seminiferous tubules, reduced spermatogonia
per tubule, reduced sperm count, and increased percentage of morphologically
abnormal sperms at all dose levels. Serious questions have been raised
regarding the design and conduct of this study (Finley et al., 1993; NTP,
1996a,b, 1997). The methods utilized by Zahid et al. were considered to
be insufficient to identify spermatogonia, likely generated nonreproducible
counts of epididymal sperm, and resulted in the biologically implausible
conclusion of reduction in spermatogonia numbers concurrent with unchanged
spermatocyte and spermatid numbers. Additional questions have been raised
with regard to the groupings of animals used and the statistical analysis
of the data. The uncertainties preclude the use of the Elbetieha and Al-Hamood
(1997) and Zahid et al. (1990) studies in the risk assessment for trivalent
chromium.

__I.A.5.
Confidence in the Oral RfD

Study — Low
Database — Low
RfD — Low

The overall confidence in this RfD assessment
is low. The principal study is rated low because of the lack of explicit
detail on study protocol and results. Low confidence in the database reflects
the lack of high-dose supporting data. The low confidence in the RfD reflects
the foregoing, but also reflects the lack of an observed effect level.
Thus, the RfD, as given, should be considered conservative, since the
MF addresses only those factors that might lower the RfD.

Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Chromium(III), insoluble salts, conducted in November 2001 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.

__I.A.7.
EPA Contacts (Oral RfD)

Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general,
at (202)566-1676 (phone), (202)566-1749 (fax), or hotline.iris@epa.gov
(Internet address).

_I.B.
Reference Concentration for Chronic Inhalation Exposure (RfC)

The inhalation Reference Concentration (RfC) is analogous
to the oral RfD and is likewise based on the assumption that thresholds
exist for certain toxic effects such as cellular necrosis. The inhalation
RfC considers toxic effects for both the respiratory system (portal-of-entry)
and for effects peripheral to the respiratory system (extrarespiratory
effects). It is generally expressed in units of mg/m3. In general,
the RfC is an estimate (with uncertainty spanning perhaps an order of
magnitude) of a daily inhalation exposure of the human population (including
sensitive subgroups) that is likely to be without an appreciable risk
of deleterious effects during a lifetime. Inhalation RfCs were derived
according to the Interim Methods for Development of Inhalation Reference
Doses (U.S. EPA, 1989) and subsequently, according to Methods for Derivation
of Inhalation Reference Concentrations and Application of Inhalation Dosimetry
(U.S. EPA, 1994). RfCs can also be derived for the noncarcinogenic health
effects of substances that are carcinogens. Therefore, it is essential
to refer to other sources of information concerning the carcinogenicity
of this substance. If the U.S. EPA has evaluated this substance for potential
human carcinogenicity, a summary of that evaluation will be contained
in Section II of this file.

__I.B.1.
Inhalation RfC Summary

Not available.

__I.B.2.
Principal and Supporting Studies (Inhalation RfC)

Not available.

__I.B.3.
Uncertainty and Modifying Factors (Inhalation RfC)

Not available.

__I.B.4.
Additional Studies/Comments (Inhalation RfC)

Data are considered to be inadequate
for development of an RfC due to the lack of a relevant toxicity study
addressing respiratory effects of Cr(III). Data from animal studies have
identified the respiratory tract as the primary target of chromium toxicity
following inhalation of hexavalent chromium and these data have been used
for development of an RfC for hexavalent chromium particulates. However,
these data do not demonstrate that the effects observed following inhalation
of hexavalent chromium particulates are relevant to inhalation of trivalent
chromium, and these data are considered to be inappropriate for development
of an RfC for trivalent chromium. The following discussion of issues related
to development of an RfC for Cr(III) has been added in 1998.

Occupational exposure to trivalent chromium and other chromium compounds
by inhalation has been studied in the chromate manufacturing and ferrochromium
industries; however, exposures all include mixed exposures to both Cr(III)
and Cr(VI). A number of epidemiological studies have demonstrated an association
between inhalation of Cr(VI) and noncarcinogenic endpoints, including
upper respiratory irritation and atrophy, changes in lung function, and
renal toxicity. These studies have been used to support the development
of an RfC for chromic acid mists (VI) and soluble chromates (VI). Data
addressing exposures to Cr(III) alone are not available, and the occupational
studies are considered to be unsuitable for development of an RfC for
Cr(III).

Several animal studies have been performed to assess the carcinogenic
potential of Cr(III) by inhalation, either by natural routes, intrapleural
injection, or intrabronchial implantation (Baetjer et al., 1959; Hueper
and Payne, 1962; Levy and Venitt, 1975; Levy and Martin, 1983). These
studies did not provide detailed reports of noncarcinogenic effects associated
with inhalation exposure to Cr(III).

Data from subchronic animal studies identify the respiratory tract as
the primary target of chromium toxicity following inhalation. Johansson
et al. (1986) exposed rabbits to aerosols of hexavalent (0.9 mg/m3
Na2CrO4)
or trivalent (0.6 mg/m3 Cr(NO3)3)
chromium for 5 days/week, 6 hours/day for 4 to 6 weeks. The number of
macrophages obtained from the lungs of the rabbits exposed to Cr(VI) was
significantly increased. While the numbers of macrophages from rabbits
exposed to Cr(III) were not increased, striking morphological changes
were observed, including round dark chromium-rich inclusions in the cytoplasm,
an increased number of cells with a smooth inactive cell surface, enlarged
Golgi apparatus, and a tendency toward elongated cell shape. The macrophages
from rabbits exposed to Cr(VI) showed less marked morphological changes
than those exposed to Cr(III). This study did not focus on endpoints that
are considered suitable for development of an RfC for Cr(III).

Johansson et al. (1980) exposed groups of four rabbits to chromium dust
at concentrations of 3.1 mg/m3 and 0.6
mg/m3 for 5 days/week, 6 hours/day for
4 weeks. Macrophages collected from rabbits exposed to the higher concentration
of chromium phagocytized significantly more chromium particles than the
controls, though the number of nonviable macrophages was less than 3%.
This study utilized small groups and did not focus on endpoints that are
considered to be suitable for development of an RfC for Cr(III).

Akatsuka and Fairhall (1934) exposed cats to chromium carbonate dust and
found no effects in terms of gross or microscopic pathology upon termination
of the experiment. Only two cats were exposed, however, and neither the
doses nor the durations of exposure were precisely defined; therefore,
these data cannot be used in quantitative risk assessment.

Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Chromium(III), insoluble salts, conducted in November 2001 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.

__I.B.7.
EPA Contacts (Inhalation RfC)

Please contact the IRIS Hotline
for all questions concerning this assessment or IRIS, in general, at (202)566-1676
(phone), (202)566-1749 (fax), or hotline.iris@epa.gov
(Internet address).

_II.
Carcinogenicity Assessment for Lifetime Exposure

Section II provides information on three aspects of the carcinogenic assessment for the
substance in question, the weight-of-evidence judgment of the likelihood that the substance is a
human carcinogen, and quantitative estimates of risk from oral exposure and from inhalation
exposure. The quantitative risk estimates are presented in three ways. The slope factor is the
result of application of a low-dose extrapolation procedure and is presented as the risk per
mg/kg-day. The unit risk is the quantitative estimate in terms of either risk per µg/L drinking
water or risk per µg/m3 air breathed. The third form in which risk is presented is a concentration
of the chemical in drinking water or air associated with cancer risks of 1 in 10,000, 1 in 100,000,
or 1 in 1,000,000. The rationale and methods used to develop the carcinogenicity information in
IRIS are deSRCibed in the Risk Assessment Guidelines of 1986 (U.S. EPA, 1986) and in the IRIS
Background Document. IRIS Summaries developed since the publication of EPA's more recent
Proposed Guidelines for Carcinogen Risk Assessment also utilize those Guidelines where
indicated (U.S. EPA, 1996). Users are referred to Section I of this IRIS file for information on
long-term toxic effects other than carcinogenicity.

_II.A.
Evidence for Human Carcinogenicity

The following discussion of issues related to potential
Cr(III) carcinogenicity has been updated in 1998.

__II.A.1.
Weight-of-Evidence Characterization

Applying the criteria for evaluating the overall weight-of-evidence for carcinogenicity to
humans outlined in EPA's guidelines for carcinogen risk assessment (U.S. EPA, 1986), trivalent
chromium is most appropriately designated a Group D -- Not classified as to its human
carcinogenicity. Using the Proposed Guidelines for Carcinogen Risk Assessment (EPA, 1996),
there are inadequate data to determine the potential carcinogenicity of trivalent chromium, as
discussed below. However, the classification of hexavalent chromium as a known human
carcinogen raises a concern for the carcinogenic potential of trivalent chromium.

__II.A.2.
Human Carcinogenicity Data

Occupational exposure to trivalent chromium and other chromium compounds by
inhalation has been studied in the chromate manufacturing and ferrochromium industries;
however, exposures all include mixed exposures to both Cr(III) and Cr(VI). The Cr(VI) species
is the likely etiological agent in reports of excess cancer risk in chromium workers. Data
addressing exposures to Cr(III) alone are not available, and data are inadequate for an evaluation
of human carcinogen potential. Two oral studies located in the available literature (Schroeder et
al., 1965; Ivankovic and Preussman, 1975) reported negative results for rats and mice. Several
animal studies have been performed to assess the carcinogenic potential of Cr(III) by inhalation.
These studies have not found an increased incidence of lung tumors following exposure either by
natural routes, intrapleural injection, or intrabronchial implantation (Baetjer et al., 1959; Hueper
and Payne, 1962; Levy and Venitt, 1975; Levy and Martin, 1983).

__II.A.3.
Animal Carcinogenicity Data

The data from oral and inhalation exposures of animals to trivalent chromium do not
support determination of the carcinogenicity of trivalent chromium. IARC (1990) concluded that
animal data are inadequate for the evaluation of the carcinogenicity of Cr(III) compounds.
Furthermore, although there is sufficient evidence of respiratory carcinogenicity associated with
exposure to chromium, the relative contributions of Cr(III), Cr(VI), metallic chromium, or
soluble versus insoluble chromium to carcinogenicity cannot be elucidated. In general, trivalent
chromium was not mutagenic in bacterial assays when tested with or without a mammalian
activation system (Venitt and Levy, 1974; Petrilli and Deflora, 1977, 1978a,b). In one study,
trivalent chromium was mutagenic in Baccillus subtilis, but this activity was low compared with
compounds of hexavalent chromium (Nakamuro et al., 1978). Taken together, these studies do
not provide adequate data to support determination of the carcinogenicity of Cr(III), and a
quantitative estimate of potential Cr(III) carcinogenicity has not been generated.

__II.D.2.
EPA Review (Carcinogenicity Assessment)

Not available.

Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Chromium(III), insoluble salts, conducted in November 2001 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.

__II.D.3.
EPA Contacts (Carcinogenicity Assessment)

Please contact the IRIS Hotline
for all questions concerning this assessment or IRIS, in general, at (202)566-1676
(phone), (202)566-1749 (fax), or hotline.iris@epa.gov
(Internet address).

International Agency for Research on Cancer (IARC). (1990) IARC monographs
on the evaluation of the carcinogenic risk of chemicals to humans: some
metals and metallic compounds. Lyon, France: World Health Organization,
IARC.

EPA's RfD/RfC and CRAVE workgroups were
discontinued in May, 1995. Chemical substance reviews that were not
completed by September 1995 were taken out of IRIS review. The IRIS
Pilot Program replaced the workgroup functions beginning in September,
1995.

04/01/1997

III., IV., V.

Drinking Water Health Advisories, EPA
Regulatory Actions, and Supplementary Data were removed from IRIS
on or before April 1997. IRIS users were directed to the appropriate
EPA Program Offices for this information.